Apatinib inhibits CYP1A2-mediated melatonin metabolism: in vitro, in vivo and molecular docking studies

Sleep disorders, particularly insomnia, are highly prevalent worldwide, and melatonin is widely used therapeutically as a key regulator of the sleep-wake cycle. This study aimed to investigate the inhibitory effect of apatinib on melatonin metabolism and its underlying mechanism. We elucidated the effect of apatinib on the metabolism of melatonin using rat liver microsomes (RLM) and human liver microsomes (HLM) and recombinant human CYP1A2 (rCYP1A2), complemented by pharmacokinetics in rats and molecular docking. In vitro , apatinib showed non-competitive inhibition in RLM (IC 50 = 15.85 μΜ) and competitive inhibition in HLM (IC 50 = 5.10 μΜ) and rCYP1A2 (IC 50 = 3.60 μΜ). IC 50 shift analysis yielded a shift ratio of 1.26 in RLM, indicating that apatinib exhibited non-time-dependent inhibition on melatonin metabolism. In vivo , apatinib markedly increased melatonin exposure with AUC (area under the curve) increased by approximately 2.8-fold (P < 0.05) and decreased clearance by 70.39% (P < 0.05), while significantly reducing the exposure of 6-hydroxymelatonin (the main metabolite of melatonin). Furthermore, molecular docking simulations revealed that both melatonin and apatinib were bound to the active pocket of CYP1A2, sharing interactions with residues Thr124 and Leu497. Overall, apatinib inhibited CYP1A2-mediated metabolism of melatonin in vitro and increased melatonin exposure in vivo , suggesting a potential clinically relevant interaction that may warrant caution and individualized dosing/monitoring when co-administered. However, the findings are limited by the use of rat pharmacokinetics and in vitro systems, and require confirmation in human clinical studies.